Treatment of mood and/or anxiety disorders by electrical brain stimulation and/or drug infusion

ABSTRACT

A system and method for introducing one or more stimulating drugs and/or applying electrical stimulation to the brain to treat mood and/or anxiety disorders uses an implantable system control unit (SCU), specifically an implantable signal/pulse generator (IPG) or microstimulator with one or more electrodes in the case of electrical stimulation, and an implantable pump with one or more catheters in the case of drug infusion. In cases requiring both electrical and drug stimulation, one or more SCUs are used. Alternatively and preferably, when needed, an SCU provides both electrical stimulation and one or more stimulating drugs. In a preferred embodiment, the system is capable of open- and closed-loop operation. In closed-loop operation, at least one SCU includes a sensor, and the sensed condition is used to adjust stimulation parameters.

The present application is a continuation-in-part (CIP) of U.S. Pat. No.6,782,292, issued Aug. 24, 2004, which patent claims the benefit of U.S.Provisional Application Ser. No. 60/212,871, filed Jun. 20, 2000. Thispatent and application are incorporated herein by reference in theirentirety.

BACKGROUND OF THE INVENTION

The present invention generally relates to implantable drug delivery andelectrical stimulation systems and methods, and more particularlyrelates to utilizing one or more implantable devices to deliverelectrical stimulation and/or one or more stimulating drugs as atreatment for mood and/or anxiety disorders.

Recent estimates indicate that more than 19 million Americans over theage of 18 years experience a depressive illness each year. The AmericanPsychiatric Association recognizes several types of clinical depression,including Mild Depression (Dysthymia), Major Depression, and BipolarDisorder (Manic-Depression). Major Depression is defined by aconstellation of chronic symptoms that include sleep problems, appetiteproblems, anhedonia or lack of energy, feelings of worthlessness orhopelessness, difficulty concentrating, and suicidal thoughts.Approximately 9.2 million Americans suffer from Major Depression, andapproximately 15 percent of all people who suffer from Major Depressiontake their own lives. Bipolar Disorder involves major depressiveepisodes alternating with high-energy periods of rash behavior, poorjudgment, and grand delusions. An estimated one percent of the Americanpopulation experiences Bipolar Disorder annually.

Significant advances in the treatment of depression have been made inthe past decade. Since the introduction of Selective Serotonin ReuptakeInhibitors (SSRIs), e.g., Prozaeantidepressant, many patients have beeneffectively treated with anti-depressant medication. New medications totreat depression are introduced almost every year, and research in thisarea is ongoing. However, an estimated 10 to 30 percent of depressedpatients taking an antidepressant are partially or totally resistant tothe treatment. Those who suffer from treatment-resistant depression havealmost no alternatives.

Electroconvulsive Therapy (ECT) is an extreme measure that is used todayto treat such patients. In ECT, a low-frequency electrical signal issent through the brain to induce a 30- to 60-second general seizure. Theside effects include memory loss and other types of cognitivedysfunction.

Repetitive Transcranial Magnetic Stimulation (rTMS) is currently beingexplored as another therapy for depression. Kirkcaldie et al. (1997)reported a greater than 50 percent response rate when applying rTMS tothe left dorsolateral prefrontal cortex of 17 depressed patients. Inaddition, a company headquartered in Houston, Tex. is currentlyexploring the application of vagus nerve stimulation totreatment-resistant depression; Rush, et al. (1999) report a successrate of 40-50 percent in a recent study of 30 patients.

Deep Brain Stimulation (DBS) has been applied to the treatment ofcentral pain syndromes and movement disorders, and it is currently beingexplored as a therapy for epilepsy. For instance, U.S. Pat. No.6,016,449 to Fischell, et al. discloses a system for the electricalstimulation of areas in the brain for the treatment of certainneurological diseases such as epilepsy, migraine headaches andParkinson's disease. However, Fischell et al. do not teach or suggestthe use of such a system for the treatment of mood disorders, such asdepression.

As was recently reported by Bejjani, et al. (1999), a patient respondedto DBS of an area near the thalamus during the therapeutic placement ofa stimulator for tremor, by lapsing into a sudden and marked depressiveepisode. The depression ceased within a couple of minutes afterstimulation was halted, and the patient demonstrated a reboundebullience. This phenomenon was repeated in the same patient severalweeks later for purposes of verification.

New functional imaging techniques have led to the identification ofseveral sites in the brain that demonstrate abnormal characteristics(e.g., hypoperfusion) in depression. Several regions of the brain havebeen identified as having decreased blood flow or metabolism indepressed patients compared to controls. In an important 1997 study,Drevets et al. reported that the subgenual prefrontal cortex (i.e., theanterior cingulate gyrus ventral to the corpus callosum) demonstrateddecreased blood flow or metabolism in patients with Major Depression andwith Bipolar Disorder compared with psychiatrically normal controls.

Similarly, Ebmeier et al. (1997), in a review of several studies,reported that the anterior cingulate gyrus demonstrates decreased bloodflow or metabolic activity in depressed patients. In a 1999 review,Davidson et al. cite several reports that indicate that the leftanterior cingulate gyrus demonstrates decreased activity in depressionand furthermore demonstrates increased activity in depressed patientswho respond to antidepressant medication.

Galynker et al. (1998) reported that decreased blood flow in the leftdorsolateral prefrontal cortex correlated with severity of negativesymptoms in depressed patients. (The left dorsolateral prefrontal cortexis the primary target of rTMS in the treatment of depression.) Drevets,in an extensive 1998 review, generalizes these results to suggest thatthe dorsal prefrontal cortex demonstrates decreased activity indepression while the ventral prefrontal cortex demonstrates increasedactivity.

Bench et al. (1992) reported decreased blood flow in the left anteriorcingulate gyrus and the left dorsolateral prefrontal cortex in depressedpatients as compared with controls, and further reported increased bloodflow in the cerebellar vermis in depressed patients withdepression-related cognitive impairment.

As stated above, Drevets reported that the ventral prefrontal cortexdemonstrates increased activity in depressed patients, and furtherreported evidence that blood flow and metabolism are abnormallyincreased in the medial thalamus in patients with Major Depression andBipolar Disorder as compared with controls. As also stated above, Benchreported abnormally increased blood flow in the cerebellar vermis indepressed patients with depression-related cognitive impairment.Abercrombie et al. (1998) reported that the metabolic rate in the rightamygdala predicts negative affect in depressed patients (although noabsolute difference was found between depressed and control subjects).

Recent studies of neurotransmitter receptors in the brains of patientswith depression also suggest possible sites of the brain that areabnormal in depression. Stockmeier et al. (1997) reported an increasednumber of serotonin receptors in the dorsal raphe nucleus of suicidevictims with major depression as compared with psychiatrically normalcontrols. Similarly, Yavari et al. (1993) reported decreased activity inthe dorsal raphe nucleus in a rat model of endogenous depression. Klimeket al. (1997) reported reduced levels of norepinephrine transporters inthe locus coeruleus in major depression. These findings corroborateexisting anatomical evidence regarding the functions of these areas.

In 1998, Saxena et al. performed a study of the pathophysiology ofobsessive-compulsive disorder. They found that at least a subgroup ofpatients with obsessive-compulsive disorder may have abnormal basalganglia development. They observed that obsessive-compulsive disordersymptoms are associated with increased activity in the orbitofrontalcortex, caudate nucleus, thalamus, and anterior cingulate gyrus.

The dorsal and median raphe nuclei, which course within the medialforebrain bundle, the dorsal longitudinal fasciculus, and the mediallongitudinal fasciculus, have long been known to have major serotonergicprojections to the limbic system. SSRI medications, which increaselevels of serotonin by blocking serotonin reuptake, provide effectivetherapy for depression, panic disorder, obsessive-compulsive disorder,and other mood and anxiety disorders.

The locus coeruleus, which lies near the floor of the fourth ventricle,has major noradrenergic projections to virtually the entire centralnervous system, including the cerebral cortex, the limbic system, andthe hypothalamus. Medications that dually block serotonin andnorepinephrine reuptake (and thus increase their levels) are effectivetherapy for depression, panic disorder, obsessive-compulsive disorder,and other mood and anxiety disorders.

Low-frequency electrical stimulation (i.e., less than 50-100 Hz), hasbeen demonstrated to excite neural tissue, leading to increased neuralactivity. Similarly, excitatory neurotransmitters, agonists thereof, andagents that act to increase levels of an excitatory neurotransmitter(s)have been demonstrated to excite neural tissue, leading to increasedneural activity. Inhibitory neurotransmitters have been demonstrated toinhibit neural tissue, leading to decreased neural activity; however,antagonists of inhibitory neurotransmitters and agents that act todecrease levels of an inhibitory neurotransmitter(s) have beendemonstrated to excite neural tissue, leading to increased neuralactivity.

High-frequency electrical stimulation (i.e., more than about 50-100 Hz)is believed to have an inhibitory effect on neural tissue, leading todecreased neural activity. Similarly, inhibitory neurotransmitters,agonists thereof, and agents that act to increase levels of aninhibitory neurotransmitter(s) have an inhibitory effect on neuraltissue, leading to decreased neural activity. Excitatoryneurotransmitters have been demonstrated to excite neural tissue,leading to increased neural activity; however, antagonists of excitatoryneurotransmitters and agents that act to decrease levels of anexcitatory neurotransmitter(s) inhibit neural tissue, leading todecreased neural activity.

Various electrical stimulation and/or drug infusion devices have beenproposed for treating neurological disorders. Some devices stimulatethrough the skin, such as electrodes placed on the scalp. Other devicesrequire significant surgical procedures for placement of electrodes,catheters, leads, and/or processing units. These devices may alsorequire an external apparatus that needs to be strapped or otherwiseaffixed to the skin.

While some patents exist that teach drug infusion and/or electricalstimulation for treatment of neurological disorders (see, e.g., U.S.Pat. Nos. 5,092,835; 5,299,569; 5,540,734; 5,975,085; 6,128,537; and6,167,311), the inventors know of no device that targets the areas ofthe brain discussed previously and elsewhere herein, and that provideschronic stimulation via a device that is implanted completely within thehead of the patient. For instance, in U.S. Pat. No. 6,128,537 (the '537patent), the infusion pump (reference number 10), the electrical signalgenerator (reference number 16), or both devices are implanted in thebody of the patient, but not in the head of the patient. In the figuresdepicting the implanted devices (FIGS. 1, 4, 5, 6, and 7), it is readilyseen that a catheter (number 22 in FIGS. 1, 4, 6, and 7) or a cable(numbered 42′ in FIG. 5) is tunneled through, at the very least, theneck of the patient in order to allow a drug or electrical stimulationto reach a desired target in the brain. Further, note column 6, lines8-10 of the '537 patent: “Signal generator 16 is implanted in a humanbody, preferably in a subcutaneous pocket located over the chest cavityor the abdomen.” There is no recognition in the '537 patent thattunneling catheters and/or cables from the chest to the head, or fromthe abdomen to the head, is a problem to be overcome.

On the other hand, U.S. Pat. No. 6,167,311 (the '311 patent) seems torecognize this problem, but offers no solution. Additionally, the '311patent acknowledges that there is no presently available solution, andthat therefore, the signal generator “must be disposed at a remote sitein the patient's body.” Note column 7, lines 57-62 of the '311 patent:“As is readily obvious to anyone who has witnessed the unnecessarysurgical procedure associated with the remote localization of the powersource, it is desirable the burr cap structure itself comprise thesignal source. However, as that option is not presently available thesignal source generator must be disposed at a remote site in thepatient's body.”

As implied by the '311 patent, there are significant problems associatedwith existing systems and methods (such as in the '537 and '311 patents)for implanting a signal generator, infusion pump, or other device at aremote site in the patient's body, which result in tunneling of acatheter(s) or cable(s) through the neck and other areas of the body.For instance, tunneling a long cable through the neck can easily lead tolead damage and breakage. In addition, the long cable routed through theneck to the brain provides an extended track for infection directly intothe brain. Also, surgical tunneling for the cable and placement of thesignal generator require general anesthesia due to the large, broad areainvolved. General anesthesia has a rather high risk of mortality andmorbidity vis-à-vis local anesthetic. In addition, the tunneling toolused for the long cable passes dangerously close to the common carotidartery and the jugular vein in the neck, with attendant risks ofbleeding and stroke.

In addition to the above and other problems not acknowledged oraddressed by the prior art, is the existence of areas in the brain ofpatients with mood and/or anxiety disorders with decreased activitycompared with control subjects. For instance, the '537 patent teachestreating anxiety by decreasing neuronal activity in certain areas of thebrain that exhibit increased activity.

BRIEF SUMMARY OF THE INVENTION

The invention disclosed and claimed herein provides systems and methodsfor introducing one or more stimulating drugs and/or applying electricalstimulation to one or more areas of the brain, preferably but notnecessarily via a “skull-mounted” or brain-implanted device. Thestimulation may be used to treat mood and/or anxiety disorders. Thefindings described earlier suggest that electrical stimulation ofspecific sites in the brain may lead to profound changes in mood. Forinstance, the functional imaging and clinical studies described abovesuggest likely targets for Deep Brain Stimulation (DBS) as a therapy fordepression.

Patients with mood and/or anxiety disorders will likely respond totherapeutic excitatory stimulation applied to those areas of the brainthat exhibit chronic decreased activity relative to psychiatricallynormal control subjects. Such excitatory stimulation is likely to beproduced by, inter alia, low-frequency electrical stimulation, anexcitatory neurotransmitter agonist, an inhibitory neurotransmitterantagonist, a medication that increases levels of an excitatoryneurotransmitter—such as Prozac® antidepressant (i.e., fluoxetinehydrochloride)—and/or an excitatory or other medication.

Patients with mood and/or anxiety disorders will likely respond totherapeutic inhibitory stimulation applied to those areas of the brainthat exhibit chronic increased activity relative to psychiatricallynormal control subjects. Such inhibitory stimulation is likely to beproduced by, inter alia, high-frequency electrical stimulation, aninhibitory neurotransmitter agonist, an excitatory neurotransmitterantagonist, a medication that increases the level of an inhibitoryneurotransmitter, and/or an inhibitory or other medication.

The treatment provided by the invention is carried out by at least asystem control unit (SCU). In one preferred form, and SCU comprises animplantable pulse generator (IPG) and implantable electrode(s) in thecase of electrical stimulation only and an implantable pump andcatheter(s) in the case of drug infusion only. However, an SCUpreferably provides both electrical stimulation and one or morestimulating drugs when necessary and desired. In this embodiment, theSCU is preferably implanted in a surgically-created shallow depressionin the temporal bone, with one or more electrode leads and/or cathetersattached to the SCU running subcutaneously to an opening in the skullwhere they pass into or onto the brain parenchyma and surroundingtissue. In other forms of SCUs, the IPG is placed in the body, forinstance, in the torso or abdominal area, and the lead(s) and/orcatheter(s) are tunneled to the stimulation location. In anotherpreferred form of an SCU, a miniature implantable neurostimulator, suchas a Bionic Neuron (also referred to as a BION® microstimulator), isimplanted. Preferred systems also include one or more sensors forsensing symptoms or other conditions that may indicate a need fortreatment.

The SCU preferably includes a programmable memory for storing dataand/or control stimulation parameters. This allows stimulation andcontrol parameters to be adjusted to levels that are safe andefficacious with minimal discomfort. Electrical and drug stimulation maybe controlled independently; alternatively, electrical and drugstimulation may be coupled, e.g., electrical stimulation may beprogrammed to occur only during drug infusion.

A preferred form of the invention uses one or more stimulating drugsand/or electrical stimulation to treat mood and/or anxiety disorders.According to one embodiment of the invention, the stimulation increasesexcitement of one or more of those areas of the brain that exhibitchronic decreased activity in patients relative to psychiatricallynormal control subjects, thereby treating or preventing such mood and/oranxiety disorder. This excitatory stimulation may be produced by, e.g.,low-frequency electrical stimulation, an excitatory neurotransmitteragonist(s) (e.g., norepinephrine), an inhibitory neurotransmitterantagonist(s), and/or a medication that increases the level of anexcitatory neurotransmitter (e.g., Prozac® antidepressant). Some uses ofthe present invention include the application to depression, panicdisorder, obsessive-compulsive disorder, and other mood and/or anxietydisorders.

According to another embodiment of the invention, the stimulationdecreases excitement of one or more of those areas of the brain thatexhibit chronic increased activity in patients relative topsychiatrically normal control subjects, thereby treating or preventingmood and/or anxiety disorders. This inhibitory stimulation may beproduced by, e.g., high-frequency electrical stimulation, an inhibitoryneurotransmitter agonist(s) (e.g., Gamma-Aminobutyric Acid, or GABA), anexcitatory neurotransmitter antagonist(s), and/or a medication thatincreases the level of an inhibitory neurotransmitter. Again, some usesinclude the application to depression, panic disorder,obsessive-compulsive disorder, and other mood and/or anxiety disorders.

According to a preferred embodiment of the invention, the electrodesused for electrical stimulation are arranged as an array on a very thinimplantable lead. The SCU is programmed to produce either monopolarelectrical stimulation, e.g., using the SCU case as an indifferentelectrode, or to produce bipolar electrical stimulation, e.g., using oneof the electrodes of an electrode array as an indifferent electrode. TheSCU includes a means of stimulating a nerve or infusing a stimulatingdrug(s) either intermittently or continuously. Specific stimulationparameters may provide therapeutic advantages for, e.g., various formsof mood and/or anxiety disorders.

The SCU used with the present invention preferably possesses one or moreof the following properties:

-   -   at least one electrode for applying stimulating current to        surrounding tissue and/or a pump and at least one catheter for        delivering a drug or drugs to surrounding tissue;    -   electronic and/or mechanical components encapsulated in a        hermetic package made from biocompatible material(s);    -   an electrical coil inside the package that receives power and/or        data by inductive or radio-frequency (RF) coupling to a        transmitting coil placed outside the body, avoiding the need for        electrical leads to connect devices to a central implanted or        external controller;    -   means for receiving and/or transmitting signals via telemetry;    -   means for receiving and/or storing electrical power within the        SCU; and    -   a form factor making the SCU implantable in a depression or        opening in the skull.

The power source of the SCU is preferably realized using one or more ofthe following options:

-   -   (1) an external power source coupled to the SCU via a        radio-frequency (RF) link;    -   (2) a self-contained power source made using any means of        generation or storage of energy, e.g., a primary battery, a        replenishable or rechargeable battery, a capacitor, a        supercapacitor; and/or    -   (3) if the self-contained power source is replenishable or        rechargeable, a means of replenishing or recharging the power        source, e.g., an RF link, an optical link, or other        energy-coupling link.

According to one embodiment of the invention, an SCU operatesindependently. According to another embodiment of the invention, an SCUoperates in a coordinated manner with other implanted SCUs, otherimplanted devices, or with devices external to the patient's body.

According to yet another embodiment of the invention, an SCUincorporates means of sensing the disorder or symptoms thereof, or othermeasures of the state of the patient. Sensed information is preferablyused to control the electrical and/or drug stimulation parameters of theSCU in a closed loop manner. According to one embodiment of theinvention, the sensing and stimulating means are incorporated into asingle SCU. According to another embodiment of the invention, thesensing means communicates sensed information to at least one SCU withstimulating means.

Thus, the present invention provides systems and methods for thetreatment of mood and/or anxiety disorders that utilizes at least onecompact, relatively inexpensive SCU. The implant site is preferablychosen to result in a relatively simple procedure, with the associatedadvantages in terms of reduced surgical time, expense, possible error,and opportunity for infection. Other advantages of the present inventioninclude, inter alia, the system's monitoring and programmingcapabilities, the power source, storage, and transfer mechanisms, theactivation of the device by the patient or clinician, the system's openloop capabilities and closed loop capabilities coupled with sensing aneed for and/or response to treatment, and coordinated use of one ormore SCUs.

BRIEF DESCRIPTION OF THE DRAWINGS

The above and other aspects, features, and advantages of the presentinvention will be more apparent from the following more particulardescription thereof, presented in conjunction with the followingdrawings wherein:

FIG. 1 depicts the lateral surface of the brain;

FIG. 2 depicts the medial surface of the brain;

FIG. 3A depicts the dorsal surface of the brain stem;

FIG. 3B is a section view through the brain stem depicted in FIG. 3A;

FIG. 4A depicts the medial surface of the head;

FIGS. 4B-4D depict coronal section views of the brain of FIG. 4A;

FIG. 5 illustrates a lateral view of the skull;

FIG. 6 illustrates internal and external components of an embodiment ofthe invention; and

FIG. 7 illustrates external components of an embodiment of theinvention.

Corresponding reference characters indicate corresponding componentsthroughout the several views of the drawings.

DETAILED DESCRIPTION OF THE INVENTION

The following description is of the best mode presently contemplated forcarrying out the invention. This description is not to be taken in alimiting sense, but is made merely for the purpose of describing thegeneral principles of the invention. The scope of the invention shouldbe determined with reference to the claims.

As described above, decreased blood flow has been noted in the leftdorsolateral prefrontal cortex (or medial frontal gyrus) of depressedpatients, and was correlated with the severity of negative symptoms.FIG. 1 depicts the lateral surface of the brain, and shows the locationof the dorsolateral prefrontal cortex 100. Similarly, the anteriorcingulate gyrus has demonstrated decreased blood flow or metabolicactivity in patients with depression, while increased activity has beennoted in the anterior cingulate gyrus of patients responding toantidepressant medication. FIG. 2 depicts the medial surface of thebrain, and indicates the location of the anterior cingulate gyrus 102.

As noted above, levels of neurotransmitters and their receptors in thebrains of patients with depression also indicate sites in the brain thatare abnormal in depression. For example, an increase in serotoninreceptors in the dorsal raphe nucleus has been implicated in suicidevictims with major depression. An unusually large population ofreceptors may indicate that serotonin levels are unusually low.Furthermore, other indications suggest that decreased activity in thedorsal raphe nucleus may be related to depression. The location of thedorsal raphe nucleus 110 is shown in FIG. 3B. In addition, reducedlevels of the neurotransmitter norepinephrine are found in the locuscoeruleus of some patients with major depression. The location of thelocus coeruleus 112 is shown in FIG. 4B.

As stated earlier, the median and dorsal raphe nuclei 110 have majorserotonergic projections to the limbic system, and the locus coeruleus112 has major noradrenergic projections to virtually the entire centralnervous system, including the cerebral cortex, the hypothalamus, and thelimbic system. In general, portions of the limbic system, which systemis credited with roles in memory, emotion, and olfaction, oftendemonstrate decreased activity in depressed patients. For instance,areas that release serotonin, and areas responsible for norepinephrineproduce less of these neurotransmitters in many depressed patients (forwhich the body may attempt to compensate with higher levels ofreceptors). Thus, via mechanisms described in more detail below, thepresent invention provides electrical stimulation, and/or excitatoryneurotransmitter agonist(s), and/or inhibitory neurotransmitterantagonist(s), and/or some other stimulating drug(s)—such as amedication that increases the level of an excitatory neurotransmitter tothese areas or increases the level of neural activity in these areas—fordepressed patients.

In other cases of depression, increased activity is found in variouslocations within the brain. For instance, the ventral prefrontal cortex120 (FIG. 1) demonstrates increased activity in some patients withdepression. In addition, blood flow and metabolism are abnormallyincreased in the medial thalamus 122 (FIG. 4B) of some patients withMajor Depression and Bipolar Disorder as compared with controls.Increased blood flow has also been seen in the cerebellar vermis 124(FIG. 4C) of patients with depression-related cognitive impairment,while the metabolic rate in the right amygdala 126 (FIG. 4D) seems topredict negative affects in some depressed patients. Also, patients withobsessive-compulsive disorder have exhibited increased activity in theorbitofrontal cortex 128 (FIG. 1), anterior cingulate gyrus 102 (FIG.2), thalamus 123 (FIG. 4B), and caudate nucleus 129 (FIG. 4D).

Other areas have shown abnormal activity in patients with mood and/oranxiety disorders: there is evidence of decreased hippocampal volume indepressed patients as compared to controls, including a loss of 5-HT(2A)receptors (the hippocampus 103 is shown in FIG. 4B); depressed patientshave been found with white matter lesions in the insula 104 (FIG. 4B),which has been correlated to poor performance on the Stroop Test;decreased activity has been observed in the right middle temporal gyrus105 (FIG. 4B) of depressed patients; and increased activity has beenobserved in the post central gyrus 106 (FIG. 1) of the dominanthemisphere of depressed patients. In addition, the following additionalareas are believed to exhibit decreased activity in depressed patients:the occipital cortex 107 (FIG. 1), temporal cortex 108 (FIG. 1),hypothalamus 109 (FIG. 2), anterior pituitary 113 (FIG. 4A), posteriorpituitary 114 (FIG. 4A), and right posterior temporal lobe 115 (FIG.4C). In most cases, areas that exhibit decreased activity in patientswith mood disorders characterized by depressed mood tend to exhibitincreased activity in patients with anxiety disorders and mood disorderscharacterized by elevated mood. On the other hand, areas that exhibitincreased activity in patients with mood disorders characterized bydepressed mood tend to exhibit decreased activity in patients withanxiety disorders and mood disorders characterized by elevated mood.However, the anterior thalamus 116 (FIG. 4D), motor cortex 117 (FIG. 1)and premotor cortex 118 (FIG. 1) may exhibit decreased activity in allpatients with mood and anxiety disorders.

The present invention provides electrical and/or drug stimulation to oneor more of the above mentioned areas as a treatment for mood and/oranxiety disorders. Herein, stimulating drugs comprise medications (someof which may excite or inhibit neural activity), anesthetic agents,synthetic or natural hormones, neurotransmitters, cytokines and otherintracellular and intercellular chemical signals and messengers, and thelike. In addition, certain neurotransmitters, hormones, and other drugsare excitatory for some tissues, yet are inhibitory to other tissues.Therefore, where, herein, a drug is referred to as an “excitatory” drug,this means that the drug is acting in an excitatory manner, although itmay act in an inhibitory manner in other circumstances and/or locations.Similarly, where an “inhibitory” drug is mentioned, this drug is actingin an inhibitory manner, although in other circumstances and/orlocations, it may be an “excitatory” drug. In addition, stimulation ofan area herein includes stimulation of cell bodies and axons in thearea.

In one preferred alternative, an implantable signal generator andelectrode(s) and/or an implantable pump and catheter(s) are used todeliver electrical stimulation and/or one or more stimulating drugs tospecific areas in the brain. One or more electrodes are surgicallyimplanted in the brain to provide electrical stimulation, and/or one ormore catheters are surgically implanted in the brain to infuse thestimulating drug(s). As used herein, stimulate, stimulation, andstimulating refer to infusion of a stimulating drug(s) and/or supplyingelectrical current pulses. As such, infusion parameters and/orelectrical current parameters are sometimes referred to herein as simplystimulation parameters, which parameters may include amplitude, volume,pulse width, infusion rate, and the like. Similarly, stimulation pulsesmay be pulses of electrical energy and/or pulses of drugs infused byvarious means and rates of infusion, such as intermittent infusion,infusion at a constant rate, and bolus infusion.

As depicted in FIG. 5, system control unit (SCU) 130 is preferably (butnot necessarily) implanted beneath the scalp, more preferably in asurgically-created shallow depression or opening in the skull 140, andmost preferably in temporal bone 142. SCU 130 preferably conforms to theprofile of surrounding tissue(s) and/or bone(s), and is small andcompact. This is preferable so that no unnecessary pressure is appliedto the skin or scalp, as this may result in skin erosion or infection.SCU 130 preferably has a diameter of no greater than 75 mm, morepreferably no greater than 65 mm, and most preferably about 35-55 mm.SCU thickness (e.g., depth into the skull) of approximately 10-12 mm ispreferred, while a thickness of about 8-10 mm or less is more preferred.

One or more electrode leads 150 and/or catheters 160 attached to SCU 130run subcutaneously, preferably in a surgically-created shallow groove(s)in the skull, to an opening(s) in the skull, and pass through theopening(s) into or onto the brain parenchyma and surrounding tissue.Recessed placement of the SCU and the lead(s) and/or catheter(s) has theadvantages of decreased likelihood of erosion of the overlying skin, andof minimal cosmetic impact.

In the case of treatment with electrical stimulation, electrode(s) 152are carried on lead 150 having a proximal end coupled to SCU 130. Thelead contains wires electrically connecting electrodes 152 to SCU 130.SCU 130 contains electrical components 170 that produce electricalstimulation pulses that travel through the wires of lead 150 and aredelivered to electrodes 152, and thus to the tissue surroundingelectrodes 152. To protect the electrical components inside SCU 130, thecase of the SCU is preferably hermetically sealed. For additionalprotection against, e.g. impact, the case is preferably made of metal(e.g. titanium) or ceramic, which materials are also, advantageously,biocompatible. In addition, SCU 130 is preferably Magnetic ResonanceImaging (MRI) compatible.

In one alternative, the electrical stimulation may be provided asdescribed in International Application Publication WO 01/60450 (the '450application), filed Feb. 12, 2001 (which claims priority to U.S.Provisional Patent Application Ser. No. 60/182,486, filed Feb. 15,2000), which application is incorporated herein by reference in itsentirety. As such, the electrical stimulation of the present inventionmay be as provided in this PCT application, which is directed to a “DeepBrain Stimulation System for the Treatment of Parkinson's Disease orOther Disorders”.

In yet another alternative, the electrical stimulation is provided byone or more implantable microstimulators, preferably of the typereferred to as BION® devices. The following documents describe variousfeatures and details associated with the manufacture, operation and useof BION implantable microstimulators, and are all incorporated herein byreference:

Application/ Filing/ Patent/ Publication Publication No. Date Title U.S.Pat. No. Issued Implantable Microstimulator 5,193,539 Mar 16, 1993 U.S.Pat. No. Issued Structure and Method of Manufacture 5, 193,540 Mar 16,1993 of an Implantable Microstimulator U.S. Pat. No. Issued ImplantableDevice Having an 5,31 2,439 May 17,1994 Electrolytic Storage ElectrodeU.S. Pat. No. Issued Implantable Microstimulator 5,324,316 Jun. 28, 1994U.S. Pat. No. Issued Structure and Method of Manufacture 5,405,367 Apr.11, 1995 of an Implantable Microstimulator U.S. Pat. No. Issued ImprovedImplantable Microstimulator 6,051,017 Apr. 18, 2000 and SystemsEmploying Same PCT Published Battery-Powered Patient ImplantablePublication Sep. 3, 1998 Device WO 98/37926 PCT Published System ofImplantable Devices For Publication Oct. 8, 1998 Monitoring and/orAffecting Body WO 98/43700 Parameters PCT Published System ofImplantable Devices For Publication Oct. 8, 1998 Monitoring and/orAffecting Body WO 98/43701 Parameters Published Micromodular Implants toProvide September, Electrical Stimulation of Paralyzed 1997 Muscles andLimbs, by Cameron, et al., published in IEEE Transactions on BiomedicalEngineering, Vol. 44, No. 9, pages 781-790.

The microstimulator, when used, is preferably implanted with a surgicalinsertion tool specially designed for the purpose, or, for instance, viaa hypodermic needle. Alternatively, the device may be implanted viaconventional surgical methods, or may be inserted using other endoscopicor laparoscopic techniques. A more complicated surgical procedure may berequired for fixing the microstimulator in place.

In one preferred embodiment, the microstimulator comprises two, leadlesselectrodes. However, either or both electrodes may alternatively belocated at the ends of short, flexible leads as described in U.S. PatentApplication Publication 2003/0114905, published Jun. 19, 2003, which isincorporated herein by reference in its entirety. The use of such leadsmay permit electrical stimulation to be directed more locally totargeted tissue(s) a short distance from the surgical fixation of thebulk of the implantable stimulator, while allowing most elements of themicrostimulator to be located in a more surgically convenient site. Thisminimizes the distance traversed and the surgical planes crossed by thedevice and any lead(s). In a preferred embodiment, the leads are nolonger than about 50 mm.

As mentioned earlier, stimulation is provided in accordance with theteachings of the present invention by electrical stimulation and/or oneor more stimulating drugs. The invention includes one or more systemcontrol units (SCU). In the case of electrical stimulation only,preferred SCUs include a microstimulator(s) and/or an implantablepulse/signal generator (IPG). In the case of drug infusion only, apreferred SCU comprises an implantable pump. In cases requiring bothelectrical stimulation and drug infusion, one or more SCUs are used.Alternatively and preferably, when needed, an SCU provides bothelectrical stimulation and one or more stimulating drugs.

In the case of treatment alternatively or additionally constituting druginfusion, catheter(s) 160 are coupled at a proximal end to SCU 130,which contains at least one pump 165 for storing and dispensing one ormore drug(s) through the catheter(s) 160. Preferably at a distal end,catheter 160 has a discharge portion 162 for infusing dosages of the oneor more drugs into a predetermined site in the brain tissue.

SCU 130 (which herein refers to IPGs, implantable pumps, IPG/pumpcombinations, microstimulators, and/or other alternative devicesdescribed herein) preferably contains electronic circuitry 170 forreceiving data and/or power from outside the body by inductive, radiofrequency (RF), or other electromagnetic coupling. In a preferredembodiment, electronic circuitry 170 includes an inductive coil forreceiving and transmitting RF data and/or power, an integrated circuit(IC) chip for decoding and storing stimulation parameters and generatingstimulation pulses (either intermittent or continuous), and additionaldiscrete electronic components required to complete the electroniccircuit functions, e.g. capacitor(s), resistor(s), coil(s), and thelike.

SCU 130 also advantageously includes a programmable memory 175 forstoring a set(s) of data, stimulation, and control parameters. Thisfeature allows electrical and/or drug stimulation to be adjusted tosettings that are safe and efficacious with minimal discomfort for eachindividual. Specific parameters may provide therapeutic advantages forvarious levels and types of mood and/or anxiety disorders. For instance,some patients may respond favorably to intermittent stimulation, whileothers may require continuous treatment for relief. Electrical and drugstimulation parameters are preferably controlled independently. However,in some instances, they are advantageously coupled, e.g., electricalstimulation may be programmed to occur only during drug infusion.

In addition, parameters may be chosen to target specific neuralpopulations and to exclude others, or to increase neural activity inspecific neural populations and to decrease neural activity in others.For example, relatively low frequency neurostimulation (i.e., less thanabout 50-100 Hz) typically has an excitatory effect on surroundingneural tissue, leading to increased neural activity, whereas relativelyhigh frequency neurostimulation (i.e., greater than about 50-100 Hz)typically has an inhibitory effect, leading to decreased neuralactivity. Similarly, excitatory neurotransmitter agonists (e.g.,norepinephrine, epinephrine, glutamate, acetylcholine, serotonin,dopamine), agonists thereof, and agents that act to increase levels ofan excitatory neurotransmitter(s) (e.g., edrophonium, Mestinon)generally have an excitatory effect on neural tissue, while inhibitoryneurotransmitters (e.g., dopamine, glycine, and gamma-aminobutyric acid,a.k.a. GABA), agonists thereof, and agents that act to increase levelsof an inhibitory neurotransmitter(s) generally have an inhibitoryeffect. (Dopamine acts as an excitatory neurotransmitter in somelocations and circumstances, and as an inhibitory neurotransmitter inother locations and circumstances.) However, antagonists of inhibitoryneurotransmitters (e.g., bicuculline) and agents that act to decreaselevels of an inhibitory neurotransmitter(s) have been demonstrated toexcite neural tissue, leading to increased neural activity. Similarly,excitatory neurotransmitter antagonists (e.g. prazosin, and metoprolol)and agents that decrease levels of excitatory neurotransmitters mayinhibit neural activity. In addition, some medications have been shownto increase neural activity, such as tricyclic antidepressants,monoamine oxidase (MOA) inhibitors and, in some cases, SSRIs, whileother medications have been shown to decrease neural activity, such asbenzodiazepines, mood stabilizers (e.g., valproic acid, carbamazepine,lithium), antipsychotics (e.g., haloperidol and atypical antipsychotics)and, in some cases, SSRIs. CCK-B receptor antagonists (Gastrinantagonists) appear to have potent anxiolytic activity and may be usefulfor treatment of anxiety disorders and mood disorders characterized byelevated mood, while CCK-B receptor agonists may be useful for mooddisorders characterized by depressed mood.

The preferred SCU 130 also includes a power source and/or power storagedevice 180. Possible power options for a stimulation device of thepresent invention, described in more detail below, include but are notlimited to an external power source coupled to the stimulation device,e.g., via an RF link, a self-contained power source utilizing any meansof generation or storage of energy (e.g., a primary battery, arechargeable battery such as a lithium ion battery, an electrolyticcapacitor, or a super- or ultra-capacitor), and if the self-containedpower source is replenishable or rechargeable, means of replenishing orrecharging the power source (e.g., an RF link).

In one preferred embodiment shown in FIG. 6, SCU 130 includes arechargeable battery as a power source/storage device 180. The batteryis recharged, as required, from an external battery charging system(EBCS) 182, typically through an inductive link 184. In this embodiment,and as explained more fully in the earlier referenced '450 PCTapplication, SCU 130 includes a processor and other electronic circuitry170 that allow it to generate stimulation pulses that are applied to thepatient through electrodes 152 and/or catheter(s) 160 in accordance witha program and stimulation parameters stored in programmable memory 175.Stimulation pulses of drugs include various types and rates of infusion,such as intermittent infusion, infusion at a constant rate, and bolusinfusion.

According to one preferred embodiment of the invention, such asdescribed in the previously referenced '450 application and as depictedin FIG. 6, at least one lead 150 is attached to SCU 130, via a suitableconnector 154. Each lead includes at least one electrode 152, and mayinclude as many as sixteen or more electrodes 152. Additional leads 150′and/or catheter(s) 160′ may be attached to SCU 130. Hence, FIG. 6 shows(in phantom lines) a second catheter 160′, and a second lead 150′,having electrodes 152′ thereon, also attached to SCU 130.

Lead(s) 150 are preferably less than 5 mm in diameter, and morepreferably less than 1.5 mm in diameter. Electrodes 152, 152′ arepreferably arranged as an array, more preferably are at least twocollinear electrodes, and more preferably at least 4 collinearelectrodes. SCU 130 is preferably programmable to produce eithermonopolar electrical stimulation, e.g., using the SCU case as anindifferent electrode, or bipolar electrical stimulation, e.g., usingone of the electrodes of the electrode array as an indifferentelectrode. A preferred SCU 130 has at least four channels and drives upto sixteen electrodes or more.

According to one embodiment of the invention, an SCU operatesindependently. According to another embodiment of the invention, an SCUoperates in a coordinated manner with other SCU(s), other implanteddevice(s), or other device(s) external to the patient's body. Forinstance, an SCU may control or operate under the control of anotherimplanted SCU(s), other implanted device(s), or other device(s) externalto the patient's body. An SCU may communicate with other implanted SCUs,other implanted devices, and/or devices external to a patient's bodyvia, e.g., an RF link, an ultrasonic link, or an optical link.Specifically, an SCU may communicate with an external remote control(e.g., patient and/or physician programmer) that is capable of sendingcommands and/or data to an SCU and that is preferably capable ofreceiving commands and/or data from an SCU.

For example, SCU 130 of the present invention may be activated anddeactivated, programmed and tested through a hand held programmer (HHP)190 (which may also be referred to as a patient programmer and ispreferably, but not necessarily, hand held), a clinician programmingsystem (CPS) 192 (which may also be hand held), or a manufacturing anddiagnostic system (MDS) 194 (which may also be hand held). HHP 190 maybe coupled to SCU 130 via an RF link 185. Similarly, MDS 194 may becoupled to SCU 130 via another RF link 186. In a like manner, CPS 192may be coupled to HHP 190 via an infra-red link 187; and MDS 194 may becoupled to HHP 190 via another infra-red link 188. Other types oftelecommunicative links, other than RF or infra-red may also be used forthis purpose. Through these links, CPS 192, for example, may be coupledthrough HHP 190 to SCU 130 for programming or diagnostic purposes. MDS194 may also be coupled to SCU 130, either directly through RF link 186,or indirectly through the IR link 188, HHP 190, and RF link 185.

In another preferred embodiment, using for example, a BIONmicrostimulator(s) as described in the above referenced patents, and asillustrated in FIG. 7, the patient 200 switches SCU 130 on and off byuse of controller 210, which is preferably handheld. Controller 210operates to control SCU 130 by any of various means, including sensingthe proximity of a permanent magnet located in controller 210, orsensing RF transmissions from controller 210.

External components for one preferred embodiment related to programmingand providing power to SCU 130 are also illustrated in FIG. 7. When itis required to communicate with SCU 130, patient 200 is positioned on ornear external appliance 220, which appliance contains one or moreinductive coils 222 or other means of communication (e.g., RFtransmitter and receiver). External appliance 220 is connected to or isa part of external electronic circuitry appliance 230 which receivespower 232 from a conventional power source. External appliance 230contains manual input means 238, e.g., a keypad, whereby the patient 200or a caregiver 242 may request changes in the parameters of theelectrical and/or drug stimulation produced during the normal operationof SCU 130. In this preferred embodiment, manual input means 238includes various electro-mechanical switches and visual display devicesthat provide the patient and/or caregiver with information about thestatus and prior programming of SCU 130.

Alternatively or additionally, external electronic appliance 230 ispreferably provided with an electronic interface means 246 forinteracting with other computing means 248, such as by a serialinterface cable or infrared link to a personal computer or to atelephone modem. Such interface means 246 thus permits a clinician tomonitor the status of the implant and prescribe new stimulationparameters from a remote location.

The external appliance(s) may advantageously be embedded in a cushion,pillow, or hat. Other possibilities exist, including a head band orother structure that may be affixed to the patient's body or clothing.

In order to help determine the strength and/or duration of electricalstimulation and/or the amount and/or type(s) of stimulating drug(s)required to produce the desired effect, in one preferred embodiment, apatient's response to and/or need for treatment is sensed. For example,when electrodes and/or catheters of SCU 130 are implanted in or near thedorsal raphe nucleus 110, signals from a serotonin level sensor builtinto SCU 130 may be recorded. (As used herein, “near” means as close asreasonably possible to targeted tissue, including touching or even beingpositioned within the tissue, but in general, may be as far as about 150mm from the target tissue.)

Alternatively, an “SCU” dedicated to sensory processes communicates withan SCU that provides the stimulation pulses. The implant circuitry 170may, if necessary, amplify and transmit these sensed signals, which maybe digital or analog. Other methods of determining the requiredelectrical and/or drug stimulation include measuring the electricalactivity of a neural population (e.g., EEG), measuring neurotransmitterlevels and/or their associated breakdown product levels, measuringmedication and/or other drug levels, hormone levels, and/or levels ofany other bloodborne substance(s), changes in one or more of these,other methods mentioned herein, and others that will be evident to thoseof skill in the field upon review of the present disclosure. The sensedinformation is preferably used to control the stimulation parameters ofthe SCU(s) in a closed-loop manner.

For instance, in one embodiment of the present invention, a first andsecond “SCU” are provided. The second “SCU” periodically (e.g. once perminute) records serotonin levels (or the level of some other substance,or an amount of electrical activity, etc.), which it transmits to thefirst SCU. The first SCU uses the sensed information to adjustelectrical and/or drug stimulation parameters according to an algorithmprogrammed, e.g., by a physician. For example, the amplitude ofelectrical stimulation may be increased in response to decreasedserotonin levels. More preferably, one SCU performs both the sensing andstimulating functions.

While an SCU 130 may also incorporate means of sensing symptoms or otherprognostic or diagnostic indicators of mood and/or anxiety disorders,e.g., via levels of a neurotransmitter or hormone, it may alternativelyor additionally be desirable to use a separate or specializedimplantable device to record and telemeter physiologicalconditions/responses in order to adjust electrical stimulation and/ordrug infusion parameters. This information may be transmitted to anexternal device, such as external appliance 220, or may be transmitteddirectly to implanted SCU(s) 130. However, in some cases, it may not benecessary or desired to include a sensing function or device, in whichcase stimulation parameters are determined and refined, for instance, bypatient feedback.

Thus, it is seen that in accordance with the present invention, one ormore external appliances are preferably provided to interact with SCU130 to accomplish one or more of the following functions:

-   -   Function 1: If necessary, transmit electrical power from the        external electronic appliance 230 via appliance 220 to SCU 130        in order to power the device and/or recharge the power        source/storage device 180. External electronic appliance 230 may        include an automatic algorithm that adjusts electrical and/or        drug stimulation parameters automatically whenever the SCU(s)        130 is/are recharged.    -   Function 2: Transmit data from the external appliance 230 via        the external appliance 220 to SCU 130 in order to change the        parameters of electrical and/or drug stimulation produced by SCU        130.    -   Function 3: Transmit sensed data indicating a need for treatment        or in response to stimulation from SCU 130 (e.g., impedance,        electrical activity of a neural population (e.g., EEG),        neurotransmitter levels, levels of neurotransmitter breakdown        products, medication levels, hormone levels, or other activity)        to external appliance 230 via external appliance 220.    -   Function 4: Transmit data indicating state of the SCU 130 (e.g.,        battery level, drug level, electrical stimulation and/or        infusion settings, etc.) to external appliance 230 via external        appliance 220.

By way of example, a treatment modality for depression is carried outaccording to the following sequence of procedures:

-   -   1. An SCU 130 is implanted so that its electrodes 152 and/or        catheter discharge portion 162 are located in the epidural space        overlying the motor cortex 117. If necessary or desired,        electrodes 152′ and/or catheter discharge portion(s) 162′ may        additionally or alternatively be located subdurally over the        motor cortex 117.    -   2. Using Function 2 described above (i.e., transmitting data) of        external electronic appliance 230 and external appliance 220,        SCU 130 is commanded to produce a series of excitatory        electrical stimulation pulses, possibly with gradually        increasing amplitude, and possibly while infusing gradually        increasing amounts of an excitatory neurotransmitter, e.g.,        glutamate, or other stimulating drug.    -   3. After each stimulation pulse, or at some other predefined        interval, any change in neurotransmitter level or electrical        activity of a neural population (e.g., EEG) resulting from the        electrical and/or drug stimulation is sensed, preferably by one        or more electrodes 152 and/or 152′. These responses are        converted to data and telemetered out to external electronic        appliance 230 via Function 3.    -   4. From the response data received at external appliance 230        from SCU 130, the stimulus threshold for obtaining a response is        determined and is used by a clinician 242 acting directly 238 or        by other computing means 248 to transmit the desired electrical        and/or drug stimulation parameters to SCU 130 in accordance with        Function 2.    -   5. When patient 200 desires to invoke electrical stimulation        and/or drug infusion, patient 200 employs controller 210 to set        SCU 130 in a state where it delivers a prescribed stimulation        pattern from a predetermined range of allowable stimulation        patterns.    -   6. To cease electrical and/or drug stimulation, patient 200        employs controller 210 to turn off SCU 130.    -   7. Periodically, the patient or caregiver recharges the power        source/storage device 180 of SCU 130, if necessary, in        accordance with Function 1 described above (i.e., transmit        electrical power).

For the treatment of any of the various types and levels of mood and/oranxiety disorders, it may be desirable to modify or adjust thealgorithmic functions performed by the implanted and/or externalcomponents, as well as the surgical approaches, in ways that would beobvious to skilled practitioners of these arts. For example, it may bedesirable to employ more than one SCU 130, each of which could beseparately controlled by means of a digital address. Multiple channelsand/or multiple patterns of electrical and/or drug stimulation mightthereby be programmed by the clinician and controlled by the patient inorder to deal with complex or multiple symptoms or dysfunctions, such asa mood disorder comorbid with an anxiety disorder.

In one preferred embodiment, SCU 130, or a group of two or more SCUs, iscontrolled via closed-loop operation. A need for and/or response tostimulation is sensed via SCU 130, or by an additional SCU (which may ormay not be dedicated to the sensing function), or by another implantedor external device.

If necessary, the sensed information is transmitted to SCU 130.Preferably, the parameters used by SCU 130 are automatically adjustedbased on the sensed information. Thus, the electrical and/or drugstimulation parameters are adjusted in a closed-loop manner to providestimulation tailored to the need for and/or response to the electricaland/or drug stimulation.

According to another preferred embodiment of the invention, theelectrical and/or drug stimulation increases excitement of one or moreof those areas of the brain that exhibit chronic decreased activity inpatients with mood and/or anxiety disorders relative to psychiatricallynormal control subjects. Such excitatory stimulation is likely to beproduced by relatively low-frequency electrical stimulation (e.g., lessthan about 50-100 Hz) and/or one or more excitatory neurotransmitters(e.g., norepinephrine, epinephrine, glutamate, acetylcholine, serotonin,dopamine), agonists thereof, inhibitory neurotransmitter antagonists(e.g., bicucilline), agents that increase the level of an excitatoryneurotransmitter (e.g., edrophonium, Mestinon), agents that decrease thelevel of an inhibitory neurotransmitter, tricyclic antidepressants, MOAinhibitors, and/or, in some cases, SSRIs. Therefore, as described above,stimulation may be applied to one or more of the anterior cingulategyrus, dorsal prefrontal cortex (especially the left dorsolateralprefrontal cortex), the dorsal and/or median raphe nuclei, and/or thelocus coeruleus.

In addition, to treat depression or other mood disorders characterizedby depressed mood, excitatory stimulation and/or one or more CCK-Breceptor agonists may be applied to one or more of the hippocampus,insula, right middle temporal gyrus, occipital cortex, temporal cortex,hypothalamus, anterior pituitary, posterior pituitary, right posteriortemporal lobe, anterior thalamus, motor cortex, and/or premotor cortex.To treat anxiety disorders and/or mood disorders characterized byelevated mood, excitatory stimulation and/or one or more CCK-B receptorantagonists may be applied to one or more of the post central gyrus,anterior thalamus, motor cortex, and/or premotor cortex.

According to yet another preferred embodiment of the invention, theelectrical and/or drug stimulation decreases excitement of one or moreof those areas of the brain that exhibit chronic increased activity inpatients with mood and/or anxiety disorders relative to psychiatricallynormal control subjects. Such inhibitory stimulation is likely to beproduced by relatively high-frequency electrical stimulation (e.g.,greater than about 50-100 Hz) and/or one or more inhibitoryneurotransmitters (e.g., dopamine, glycine, GABA), agonists thereof,excitatory neurotransmitter antagonists (e.g., prazosin, metoprolol),agents that increase the level of an inhibitory neurotransmitter, agentsthat decrease the level of an excitatory neurotransmitter, localanesthetic agents (e.g., lidocaine), benzodiazepines, mood stabilizers(e.g., valproic acid, carbamazepine, lithium), antipsychotics (e.g.,haloperidol and atypical antipsychotics) and/or, in some cases, SSRIs.Thus, stimulation may also/instead be applied to one or more of theventral prefrontal cortex, the cerebellar vermis, the amygdala, theorbitofrontal cortex, the caudate nucleus, the medial thalamus, and/orother areas of the thalamus.

In addition, inhibitory stimulation and/or one or more CCK-B receptoragonists may be applied to the post central gyrus to treat depression orother mood disorders characterized by depressed mood. To treat anxietydisorders and/or mood disorders characterized by elevated mood,inhibitory stimulation and/or one or more CCK-B receptor antagonists maybe applied to one or more of the hippocampus, insula, right middletemporal gyrus, occipital cortex, temporal cortex, hypothalamus,anterior pituitary, posterior pituitary, and/or right posterior temporallobe.

In yet another alternative, sensing means described earlier may be usedto orchestrate first the activation of SCU(s) targeting one or moreareas of the brain, and then, when appropriate, the SCU(s) targetinganother area and/or by a different means. Alternatively, thisorchestration may be programmed, and not based on a sensed condition.

Thus, the present invention provides systems and methods for thetreatment, control, and/or prevention of mood and/or anxiety disordersthat utilize one or more compact, relatively inexpensive SCUs. Theimplant site results in a relatively simple procedure, with theassociated advantages in terms of reduced surgical time, expense,possible error, and opportunity for infection and other complications.Other advantages, inter alia, of the present invention include thesystem's monitoring and programming capabilities, the power source,storage, and transfer mechanisms, the activation of the device by thepatient or clinician, the system's open-loop capabilities andclosed-loop capabilities coupled with sensing a need for and/or responseto treatment, and coordinated use of one or more SCUs.

While the invention herein disclosed has been described by means ofspecific embodiments and applications thereof, numerous modificationsand variations could be made thereto by those skilled in the art withoutdeparting from the scope of the invention set forth in the claims.

1.-26. (canceled)
 27. A method of treating a patient with an anxietydisorder and/or a mood disorder characterized by elevated mood,comprising: implanting at least one system control unit in the patient,wherein the at least one unit controls the delivery of at least onestimulus to at least one area of the brain affecting an anxiety disorderand/or a mood disorder characterized by elevated mood; applying the atleast one stimulus to the at least one area of the brain in order to atleast in part alleviate symptoms of the anxiety and/or mood disorder ofthe patient being treated, wherein the at least one stimulus decreasesexcitement of the at least one area of the brain affecting the anxietyand/or mood disorder that exhibits chronic increased activity; andwherein the at least one stimulus is applied to one or more of thehippocampus, insula, right middle temporal gyrus, occipital cortex,temporal cortex, hypothalamus, anterior pituitary, posterior pituitary,and right posterior temporal lobe.
 28. The method of treatment of claim27 wherein the system control unit is connected to at least oneelectrode, and wherein the stimulus comprises electrical stimulationdelivered via the at least one electrode.
 29. The method of treatment ofclaim 27 wherein the system control unit is connected to at least onecatheter, and wherein the stimulus comprises stimulation via one or moredrugs delivered through the at least one catheter.
 30. The method oftreatment of claim 27 wherein the system control unit is connected to atleast one electrode and to at least one catheter, and wherein thestimulus comprises both electrical stimulation delivered via the atleast one electrode and stimulation via one or more drugs deliveredthrough the at least one catheter.
 31. The method of treatment of claim27 wherein implanting the at least one system control unit in thepatient comprises implanting the at least one system control unit in theskull and/or brain of the patient.
 32. The method of claim 27 whereinthe stimulation is relatively high-frequency electrical stimulation. 33.The method of claim 27 wherein the stimulation in drug stimulationprovided by at least one of an inhibitory neurostransmitter agonist, anexcitatory neurotransmitter antagonist, an agent that increases thelevel of an inhibitory neurotransmitter, an agent that decreases thelevel of an excitatory neurotransmitter, a local anesthetic agent, andan inhibitory medication.
 34. The method of claim 33 wherein theinhibitory drug is at least one of a benzodiazepine, a mood stabilizer,an antipsychotic, and an SSRI.